Project Summary/Abstract The evolving field of regenerative medicine integrates chemistry, engineering, biology and medicine to repair, replace, or enhance tissue or organ function lost due to disease, injury, or aging. It requires complex approaches to integrate living cells and proper biological signals with 3-dimensional scaffolding materials. The difficulty in designing tissue scaffolds and implants with properties that simultaneously enable their safe delivery / secure fitting to a target tissue and their proper long-term function in physiological environment has been a major roadblock in reducing regenerative medicine concepts to clinical practices. The proposed EUREKA project uses an innovative nanostructured material design platform to develop shape memory tissue scaffolds and implants that possess tunable mechanical strength, defined biochemical microenvironment, and minimally invasive delivery and self-fitting tissue docking capability. In addition to designing high-modality organic-inorganic nanostructured building blocks to encode rich functional information, an innovative strategy for enhancing shape memory behavior through the confinement of polymer chain-chain interactions between rigid nanoparticle anchors is proposed. If validated, this new platform can open a new paradigm for designing high performance shape memory composites for a wide range of applications. By generating patient-specific and defect-specific medical implants and tissue grafts that precisely fit and conform to each individual defects physically and biochemically, it will have paradigm-changing impact on personalized intervention of a broad range of medical conditions ranging from skeletal defects to cardiovascular diseases and stroke. In addition, with the ability to spatially present and temporally release signaling molecules to and from the 3-dimensional scaffolds with defined mechanical cues, these intelligent materials can also enable informative in vitro studies of complex molecular signaling events or serve as valuable 3-dimensional tissue models for drug discovery. Due to the novelty of this concept, its inherent risks, and enormous medical impact and scientific potential, this project is an excellent candidate for the EUREKA funding mechanism. Within the 4-year project period, we expect to generate a library of 3-dimensional shape memory scaffolds with wide-ranging porosities, mechanical strengths, and signaling molecule encapsulation/release characteristics suitable for applications ranging from self-fitting synthetic bone grafts to deployable drug-eluting stents. We will validate the feasibility of this nanostructured material design platform using both in vitro cell culture models and a small animal critical defect model, choosing a weight-bearing shape memory bone tissue scaffold as the initial proof-of-concept application.